PB1901: NOT ALL VARIANTS OF ACUTE PROMYELOCYTIC LEUKEMIAS ARE RESISTANT TO RETINOIDS.
Authors: Mehndi Dandwani, Teena Thomas, Maun Baral, Madhura Hanmantgad, Fnu Sandeep
Journal: HemaSphere (2023)

Topic: 4. Acute myeloid leukemia - Clinical Background: Acute Promyelocytic Leukemia (APL) is defined by chromosomal translocation t(15;17), creating promyelocytic leukemia/retinoic acid receptor alpha (PML/RARA) fusion protein. However, variant translocations involving RARA have been identified, including t(11;17) which are known to be refractory to all-trans retinoic acid (ATRA). Aims: To highlight a case of a rare variant of APL (APLv) involving promyelocytic leukemia zinc finger PLZF/RARA translocation; t(11;17) (q23;q21) that showed morphologic complete remission on induction with ATRA, arsenic trioxide (ATO) and idarubicin. Methods: A 39-year-old male presented with complaints of sore throat, fever and odynophagia and was admitted for a peritonsillar abscess with tonsillitis. He was found to have persistent leukocytosis despite treatment with IV ampicillin–sulbactam. Peripheral blood smear (PBS) showed leukocytosis with neutrophilia and marked left shift (promyelocytes, myelocytes, metamyelocytes, bands) with some atypical-looking myeloid cells. Fluorescence in situ hybridization (FISH) of PBS showed 89% of cells positive for rearrangement of RARA but negative for PML/RARA rearrangement. He was started on ATRA. He underwent bone marrow (BM) biopsy with flow cytometry showing about 80% abnormal immature myeloid population that expressed CD117, CD13, CD33, CD38 and CD64, negative for CD34 and HLA-DR, phenotypically compatible with APL. Cytogenetics was positive for t(11; 17) (q23;q21), with PLZF-RARA fusion. Next-generation sequencing showed no targetable mutations. He underwent sperm banking. He was started on induction therapy with ATRA at 45mg/m2/day in 2 divided doses, systemic chemotherapy with 4 doses of idarubicin (12mg/m2 on day 1,3,5,7), followed by arsenic trioxide (ATO) on day 8 at 0.15 mg/kg IV daily until hematological response. He received a brief course of cytoreductive therapy with hydroxyurea 1500 mg twice daily during the initial phase of treatment for high-risk APLv (white cell count >10 × 10⁹/l). The patient experienced no complications of coagulopathy and received cryoprecipitate as needed for fibrinogen levels <100 mg/dl. His hospital course was complicated with fever and pleuritic chest pain. EKG showed diffuse ST elevations in anterolateral and inferior leads with normal troponin levels consistent with pericarditis. His echocardiogram showed no evidence of pericardial effusion. He was managed as differentiation syndrome with dexamethasone and symptomatic improvement within 24 hours of initiation of steroid therapy. Results: BM biopsy at cell count recovery with platelets (> 100x109/L) and neutrophils (> 1x109/L) post-induction showed complete remission with a morphologic response (<5% blasts) and normal cytogenetic analysis. Despite the achievement of complete morphologic remission, there were concerns for the relative refractoriness of the APLv to ATO+ATRA alone, although scant with fewer data on ATO sensitivity. Thus, a chemotherapy-based consolidation approach was chosen vs ATRA+ATO alone. PETHEMA (LPA2005) high-risk APL protocol (Sanz M et al; Blood. 2010;115(25):5137-5146) based consolidation regimen was chosen with addition of cytarabine combined with ATRA and idarubicin in the 1st and 3rd consolidation cycles for a total of 3 monthly cycles. Idarubicin was omitted for the 3rd cycle due to the lifetime anthracycline limit. He is currently receiving maintenance therapy with methotrexate, 6-Mercaptopurine and ATRA and is in remission now. Summary/Conclusion: Thus, not all variants of APL are ATRA-resistant with some being the odd man out among their rarest pool of APL variants.Keywords: ALL-trans retinoic acid (ATRA), Acute promyelocytic leukemia, Arsenic trioxide, PML